In the last several years, significant progress has been made in understanding the relevance of the T cell immune response to the clearance of the Gram-negative pathogen Salmonella typhimurium, a category B pathogen. We have established that CD8+ T cells are essential to the protective immune response against infection with S. typhimurium, and these studies led to the identification of peptide epitopes recognized by bacteria-specific CD8 effector T cells. In this revised competitive renewal, we build on these initial observations and utilize a natural infection model. This model has allowed us to identify novel intestinal intraepithelial lymphocytes (ilELS) that expand following infection. These cells may represent a early element of the host mucosal response to infection. In the next five years, we will focus our efforts on the following Aims: Aim 1. What are the characteristics of the novel CD8+ alpha/beta expressing Intraepithelial Lymphocytes (ilELs) that are induced in the small intestine after oral infection with S. typhimurium? Specifically, we will determine their TCR usage, kinetics of appearance and define the recognition properties of these T cell subsets. Aim 2. What role does this novel CD8+/expressing ilELs play in the host immune response to S. typhimurium? Aim 3. Do bacteria, that display defined differences in cellular tropisms (e.g., dendritic cells vs. macrophages vs. epithelial cells), vary in their ability to stimulate host CD8+ T cell-mediated immune responses? The studies contained in this proposal are designed to address the immune elements that contribute to the clearance of infection and the generation of protective immunity to the Gram-negative pathogen Salmonella typhimurium. We hope to apply this in formation to the design of vaccine strategies that will evoke potent protective immunity as identify targets for immunotherapeutic strategies. We argue that such studies may aid in the design of novel strategies that can be used to stimulate immunity to an organism considered a bioterrorist threat. Also, such studies may contribute to understanding the etiological link between infection with gram-negative! pathogens in the development of autoimmune disease. Given that many of the cellular receptors in the mouse model have human counterparts, we argue that this murine model will yield valuable information that may be applied to the human setting.